The bladder is a membranous muscular organ used for storage of urine, maintenance of urine composition, and elimination of urine at appropriate intervals. Its structure is composed of four basic layers, comprising an epithelium, lamina propria, muscularis propria (i.e., detrusor muscle), and perivesical soft tissue. The epithelium, which lines the bladder and is in contact with the urine, is referred to as the transitional epithelium or urothelium and functions to maintain a chemical gradient between the urine and blood. Lying underneath the epithelium is the lamina propria, a layer of connective tissue and blood vessels. A layer of thin and often discontinuous smooth muscle, the muscularis mucosae, lies within the lamina propria. This superficial layer of smooth muscle is distinctive from the muscularis propria or detrusor muscle, which is a deep muscle layer consisting of thick smooth muscle bundles that form the wall of the bladder. Perivesical soft tissue comprises the outer layer of the bladder and consists of fat, fibrous tissue and blood vessels. Dysfunctions of the bladder are common and can have debilitating effects on the affected individual.
Interstitial cystitis (IC) is a bladder disease of unknown etiology. Clinical symptoms include chronic urinary frequency, urgency, nocturia, and bladder/pelvic pain. Although originally thought to primarily affect middle-aged women, IC occurs in both sexes and in all ages.
The literature describes two types of IC based on cytoscopic examinations of the bladder. Non-ulcerative IC, the most common form, is characterized by presence of glomerulations (ie., pinpoint bleeding) upon hydrodistention of the bladder. Ulcerative IC is seen in about 10% of patients and is defined by the presence of Hunner's ulcers, which are star shaped mucosal ulcerations on the bladder wall. A significant number of IC patients, however, show no symptoms upon cytoscopic examination, and there is no reliable correlation between severity of cytoscopic findings and clinical symptoms.
Histopathological indications are a denuded epithelium, prominent leukocyte and plasma cell infiltration in the lamina propria, vascular congestion, and fibrosis of the detrusor layer (MacDermott, J. P. et al., J. Urol. 145: 274-278 (1991)). These features, however, appear to be restricted to a small subgroup of patients diagnosed with pyuria and small bladder capacity. Neutrophils are seen only in association with ulcerations (Lynes, W. L. et al., Amer. J. Surg. Pathol. 14: 969-976 (1990)). Macrophages are rarely present in the inflamed sites, and inflammatory infiltrates are infrequent in the detrusor layer. Chronic inflammation is absent in many patients who show clinical symptoms. Because of this varying, inconsistent histopathology, diagnosis of IC may use a constellation of indications.
Various theories exist on causes of IC, including compromised epithelial integrity, infection, neurogenic inflammation, mast cell activation, and autoimmunity. Several studies suggest increased permeability of the epithelium in IC patients (see, e.g., Lavelle, J. P. et al., Am. J. Physiol. Renal. Physiol. 278: F540-F553 (2000)). Affected bladders show qualitative changes in mucosal glycosaminoglycan, ultrastructural defects in urothelium, and increased transport of urea. Pain and urgency occur in a majority of patients with IC upon intravesical instillation with KCl solution, suggestive of compromised epithelial structure. Similarly, a urea solution instilled into the bladder and then later drained has lower urea concentrations in IC patients versus control groups, indicating increased mucosal permeability in affected subjects.
Although infection is also suspected as an etiological agent, PCR analyses of biopsy samples have proved negative for presence of pathogenic bacteria (Keay, S. et al., J. Urol. 159: 280-283 (1998)). In addition, analysis for bacteria, fungi, and viruses in IC afflicted bladders has not detected any differences from unaffected patients (Duncan, J. L. et al., Urology 49: 48-51 (1997)). At present, evidence for a pathogenic cause is lacking.
Several studies suggest a role in IC of neurogenic inflammation involving neuropeptide Substance P and its receptor, neurokinin-1 receptor (NK-1 receptor). Stimulation of sensory neurons results in release of Substance P, which is known to trigger release of inflammatory modulators and histamine by mast cells. In animal models of IC, Substance P level is elevated in the bladder and urine (Hammond, T. G. et al., Ann J. Physiol. Renal Physiol 278: F440-F451 (2000)), and biopsies show increased density of Substance P containing nerve fibers. Intravesical administration of Substance P causes bladder inflammation in mice while desensitization of sensory fibers decreases urinary bladder hyperflexia. NK-1 receptor antagonists abrogate or reduce Substance P mediated cystitis, and bladder inflammation is attenuated in NK-1 receptor knockout mice (Saban, R. et al., Amer. J. Path. 156: 775-780 (2000)). Further suggestion for involvement of the Substance P pathway is indicated by increased expression of NK-1 receptor seen in bladder biopsies of patients with IC (Marchand, J. E. et, al., Br. J. Urol. 81:224-228 (1998)).
The postulated role of Substance P implicates mast cells in the physiological processes leading to IC. IC bladders have increased numbers of mast cells in the detrusor and submucosal layers, and elevated numbers of mast cells are found near Substance P containing sensory nerves. Mastocytosis is present in 30-65% of IC patients while levels of histamine and tryptase are elevated. Interestingly, experimentally induced bladder inflammation is absent in mast cell deficient mice Kit(W)/Kit(W-v) (see Saban, R. et al., Physiol. Genomics 10: 35-43 (2001); Saban, R. et al., Am. J. Physiol. Renal Physiol. 282: F202-F210 (2002)). It is theorized that elevated number of mast cells in conjunction with sensory peptides lead to mast cell mediated immune reactions. The predominant presence of mast cells in the detrusor layer, however, does not explain the compromised state of epithelium in IC. Moreover, very few inflammatory cells are found in the detrusor layer.
An autoimmune cause is suspected in IC because of an epidemiological association between IC and autoimmune diseases, such as lupus erythematosus, allergic asthma, multiple sclerosis, inflammatory bowel disease, and Sjorgren's disease. These autoimmune diseases are overrepresented in IC afflicted patients. However, lymphocyte phenotypes (e.g., CD4/CD8 cell ratios) in the peripheral blood of IC subjects are normal, in contrast to findings for autoimmune diseases lupus erythematosus, primary biliary cirrhosis, or multiple sclerosis (MacDermoft, J. P. et al., J. Urol. 145: 274-278 (1991)). Histological studies of bladder biopsies show increased lymphocyte infiltrates, but are contradictory as to the type of lymphocytes present in the various structures of the bladder (MacDermoft et al., supra.; Hanno, P. et al., J. Urol. 143: 278-281 (1990)). Although early studies also indicated presence of circulating bladder specific antibodies, subsequent results have shown conflicting data, suggesting that these humoral indications may be an indirect consequence of tissue damage. Consequently, no clear link has been established between immune system dysregulation and IC.
The presence of lymphocyte infiltrates and increased number of mast cells suggests some role of inflammatory network in IC. Conditioned medium obtained from cultured, activated mast cells can induce in an urothelial cell line synthesis of cytokines TNF-α, IL-1 b, and IL-8, and adhesion molecule ICAM-1 (Batler, R. A. et al., J. Urol. 168: 819-825 (2002)). On the other hand, inflammatory mediators are not significantly elevated in the urine of patients diagnosed with IC. Urinary concentrations of cytokines IL4, IL-10, IL-12, TNF-α, hGM-CSF, IL-1b and IFN-γ; prostaglandins E2, D2, and F2a; and thromboxanes are no different from unaffected individuals (Felson, D. et al., J. Urol. 152: 355-361 (1994); Peters, K. M. Adult Urology 54: 450-453 (1999)). Some patients with active IC show elevated levels of cytokines IL-2, IL-6, and IL-8, but not of major inflammatory cytokines TNF-α or IFN-γ (Peters, K. M., supra). The predominance of mast cells in the detrusor layer, which lacks inflammatory infiltrates, and the general absence of macrophages complicate the link between the inflammatory cascade and IC. Interestingly, BCG (bacilli Calmette-Guerin), which shows some efficacy in ameliorating the symptoms of IC, is known to increase levels of IL-1, IL-2, IFN-γ and TNF-α in urine following intravesical instillation in the bladder (see Peters, K. M. et al., supra; Bohle, A. J. Urol 144: 5964 (1990)).
Treatments for IC are few and varied, particularly given the unknown etiology of the disease. BCG, as indicated above, has shown some efficacy in treating IC symptoms. Pentosan polysulfate sodium (Elmiron®), a heparin derivative, is believed to help repair and protect damaged bladder epithelium, but also inhibits release of histamine from mast cells (Chiang, G. et al., J. Urol. 164(6):2119-2125 (2000)). Dimethyl sulfoxide (DMSO) reduces bladder pain and is suggested to have an anti-inflammatory effect. Immunosuppressive agents cyclosporin (Forsell, T. et al., J. Urol. 155:1591-1593 (1996)) and methotrexate (Moran, P. A. et al., Aust N Z J Obstet Gynaecol. 39: 468-471 (1999)) provides variable effectiveness in ameliorating IC symptoms. Given the lack of standard, effective therapy for IC, there is a need in the art for other efficacious, therapeutic treatments. Accordingly, the present invention provides methods and compositions for the treatment of IC.